Primary nephrotic syndrome is the dominant cause of acquired kidney disease in children, with significant morbidity and mortality from the disease and its treatment, and a substantial risk of kidney failure. Yet, there is limited information on te natural history of primary glomerular disease in children, risk factors for poor outcomes and differential response to therapy. There is clearly a need for better therapies given the side effects and limited response to current therapies. Our long-term goal is to define specific molecular pathways that mediate cell injury in order to develop more targeted, effective, and less toxic therapies for glomerular disease. The overall objective of this proposal is to successfully recruit 600 children with four glomerular diseases (Minimal Change Nephrotic Syndrome [MCD], Focal Segmental Glomerulosclerosis [FSGS], IgA Nephropathy [IgAN], and Idiopathic Membranous Nephropathy[IMN]) into a longitudinal cohort study that will include integrated proteomic and metabolic analyses of highly phenotyped biological samples to identify predictive biomarkers for pediatric glomerular disease. Our central hypothesis is that integrated proteomic and metabolic analyses from clinically phenotyped sequential biological samples will identify novel biomarkers that can predict both clinical outcomes and therapeutic responses for pediatric glomelular disease, and identify molecular targets for future therapies. Thus, the rationale for this proposal is that recruitment and clinical phenotyping of a very large cohort of children with glomerular disease, combined with innovative pilot studies integrating proteomic and metabolomic analyses from sequential biological samples, will identify novel biomarkers that can predict both clinical outcomes and therapeutic responses, as well as identify molecular targets for future therapies. To test our central hypothesis, we propose the following Specific Aims: 1) To successfully recruit 600 children with MCNS, FSGS, IgAN, and IMN into a longitudinal cohort study that includes sequential detailed clinical phenotyping, combined with standardized collection, processing, and storage of serum, plasma and urine samples. 2) To define protocols that integrate proteomic and metabolic analyses of highly phenotyped biological samples in order to identify biomarkers able to predict clinical outcomes and therapeutic responses for pediatric glomerular disease. Metabolomics and proteomics will identify biomarkers that provide information on disease prognosis and predicted response to therapy, which will support the design and implementation of clinical trials. Biomarker identification will guide the development of more targeted, effective, and less toxic therapies for one of the most common kidney diseases in the US.